| Summary: | 碩士 === 國立臺灣大學 === 毒理學研究所 === 86 === Abstract
Territrem B (TRB), a tremorgenic mycotoxin isolated from
rice cultures of Aspergillus terreus 23-1, is a potent, irreversible
and noncovalent inhibitor of eel acetylcholinesterase(AChE, EC 3.1.1.7)
Here a computer docking simulation study was carried out with the aim
to understand the inhibition mechanism of TRB on AChE. The docking results
indicated that both the aromatic head or the non-aromatic tail moiety of TRB
inserted into the a ctive gorge of AChE. However, from a combination
of analysis on both structural and biochemical data, a low-energy model, T2 ,
latter the former configuration,appears to be most consistent
with the experimental
evidence. Interestingly, in the T2 model, no contacts between TRB and the
catalytic residues of AChE were found, and TRB, by insection,
blocked the access
to the gorge, while inducing conformational change
of several aromatic residues of the gorge structure and
contraction of the gorge gate.
This simulation result is in agreement with kinetic data,
indicating that hydrolysis
of the substrate acetylcholine by AChE could be hindered by an
irreversible TRB blocking in the gorge.
The potent inhibition of AChE by a very low concentration of TRB could also be
attributed to favorable hydrophobic and hydrogen-bonded
interactions between TRB and AChE.
These favorable interactions include the hydrophobic face of
TRB interacting with Trp84,
Trp279, and Phe334, and the hydrophilic face of TRB hydrogen
bonding with Tyr70,Tyr121.
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